Cancer remains a major threat to human health, and millions of people die from cancers every year in the world. Although many methods of treatment, such as surgery and radiation therapy are available, curative ratio generally is low. Presently, the use of pharmaceutical chemicals remains one of the most effective cancer therapies.
Purine or pyridine derivatives are known to have anti-viral or anti-cancer activities, see e.g. EP 173624, EP 253412, EP 353955, WO 9201698, and EP 481214.
In natural or synthetic nucleotide derivatives, the pyridine or purine or other heterocylic group is located on the 1 position of the saccharide ring (corresponding to the 2 position of a hydroxyl-substituted furan derivative). These substitutes have recently been reported to have anti-cancer or antivirus activities.
Another group of derivatives, O6-alkyl purine derivatives, are known to have the ability to inhibit the activity of O6-alkylguanine-DNA alkyltransferase (AGT), thereby enhancing the effectiveness of alkylating agent as tumor chemotherapy agents. Although the cancer cell killing mechanism of the O6-methyl guanine is not clear, it is generally understood that the mechanism of the O6-chloroethyl guanine is via a cycloethidene guanine intermediate, which cross links the DNA double strand. This linkage can be eliminated or prevented via an ATPase mediated de-chloroethylation, e.g. via AGT. Methods for antagonizing AGT have been reported in e.g. U.S. Pat. No. 5,091,430 and WO 9113898.
N-substituted purine derivatives have been known. For example, N6-disubstituted purine derivatives are described in U.S. Pat. No. 4,853,386, which can be used to treat allergies. 6-cyclopropylamino-9H purine derivatives are described in JP 2003-55377 and JP 2003-119197, which have antivirus activities. Glycosylated purine derivatives which have anti-inflammatory properties are described in J. Org. Chem (2004, 69:3212-3215). N2-butylphenyl-2′-desoxypurine derivatives are described in J. Med. Chem (1984, 27:175-181), which have the activity of inhibiting eukaryotic DNAα polymerase. 2, 6, 9-substituted purine derivatives are described in the Tetrahedron Letters (1998, 39:1827-1830).
None of the above mentioned compounds, however, have been shown to have anti-cancer activities or the ability to inhibit abnormal cell growth. Accordingly, there is a need for N2-substituted purine derivatives that may be used as anti-cancer agents.